HU207332B - Process for producing anthelnintic benzthiazols and compositions containing them - Google Patents

Abstract

Anthelmintically active compounds of the formula I have been described wherein
R₁ is hydrogen, halogen, C₁-C₂-alkyl, C₁-C₂-haloalkyl, nitro, C₁-C₂-alkoxy or the group SO _n R, wherein R is C₁-C₂-alkyl or phenyl and n is 0, 1 or 2 stands;
R₂ is hydrogen, halo, C₁-C₂ alkyl, C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy or C₁-C₂ alkoxy;
R₃ is hydrogen or C₁-C₂ alkyl;
R₄ is hydrogen or C₁-C₂ alkyl;
R₅ is hydrogen, halogen or C₁-C₅ alkyl;
R₆ is hydrogen, halogen or C₁-C₅ alkyl;
R₇ is hydrogen, halogen, C₁-C₂ alkyl, nitro, C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy or C₁-C₂ alkoxy;
R₈ is hydrogen, halogen, C₁-C₂ alkyl, C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy or C₁-C₂ alkoxy;
R₉ is hydrogen, halogen, C₁-C₂ alkyl, C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy or C₁-C₂ alkoxy;
R₁₀ is hydrogen, halogen, nitro, NCS, OCF₃, C₁-C₂ alkyl or C₁-C₂ alkoxy;
R₁₁ is hydrogen, halogen, nitro, NCS, OCF₃, C₁-C₂ alkyl or C₁-C₂ alkoxy; or
R₁₀ and R₁₁ together form an -O (CH₂) _m O-bridge, where m is 1, 2 or 3,
including their physiologically acceptable acid addition salts, as well as their preparation and use and novel intermediates.

Description

FIELD OF THE INVENTION The present invention relates to novel anthelmintic substituted anthranilic acid derivatives and to anthelmintic anthelmintic agents, particularly against nematodes, tapeworms and sucking worms, for use in anthelmintic warm-blooded animals, particularly mammals and preferably domestic and farm animals.

The novel anthranilic acid derivatives, including their physiologically tolerable acid addition salts, are characterized by the following formula (I):

R 1 is halogen or -SR wherein R is C 1-6 alkyl;

R _{2 is} hydrogen or halogen;

R _{3 is} hydrogen;

R _{4 is} hydrogen;

R5 is hydrogen or halogen;

R _{6 is} hydrogen;

R7 is halogen;

R _{8 is} hydrogen;

R _{9 is} hydrogen;

R 10 is hydrogen, halogen, trifluoromethyl, trifluoromethoxy, or nitro;

R _{n is} hydrogen, halogen, C 1-2 haloalkoxy, or C 1-2 alkoxy; obsession

R ₁₀ and R _n together _form a -O (CH ₂₎ form a bridge having the formula O _2, whereby the benzothiazolyl group in position 4.

The alkyl group as a single group or as part of another substituent, depending on the number of carbon atoms described herein, represents straight or branched chain groups such as methyl, ethyl, n-propyl, isopropyl, η-butyl, sec-butyl, tertiary -butyl, isobutyl, b. The haloalkyl group can range from a simple halogenated alkyl group to a perhalogenated alkyl group such as chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, bromo, methyl, dibromomethyl, tribromomethyl, iodomethyl, triiodomethyl, chlorofluoromethyl, chlorobromomethyl, fluorobromochloromethyl, pentafluoroethyl, , 2-chloroethyl, 1-chloroethyl, pentachloroethyl, 1-fluoro-2-dichloroethyl, preferably trifluoromethyl. The halogen atom here and hereinafter is fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine, but above all chlorine.

A preferred group of compounds of formula I are those wherein R 1 is a 4-position halogen atom, especially a 4-position chlorine atom;

R _{2 is} hydrogen and the other substituents are as defined for formula (I).

Preferably, furthermore, the compounds of formula I wherein

R 1 is halogen or methylthio, preferably 4-position halogen, especially 4-position chloro;

R _{2 is} hydrogen or halogen, preferably 5-halogen, especially 5-chloro;

R _{3 is} hydrogen;

R _{4 is} hydrogen;

R _{5 is} hydrogen or halogen;

R _{6 is} hydrogen;

R _{7 is} halogen;

R _{g is} hydrogen;

R _{9 is} hydrogen;

R _{10 is} halogen; and

R _{n is} hydrogen.

Some preferred compounds of formula (I) include: 5-chloro-2 - [(4-chlorophenylsulfonyl) amino] benzoic acid [4- (6-trifluoromethoxybenzothiazolyl-2-). oxy) propionamide]; 5-chloro-2 - [(4-chlorophenylsulfonyl) amino] benzoic acid [4- (6-fluoro-5- (or 7) -chlorobenzothiazolyl-2-oxy) anilide]; 5-chloro-2 - [(4-chlorophenyl-sulfonyl) amino] benzoic acid [4- (6-chloro-2-benzothiazolyl) propionamide];

3,5-Dichloro-2 - [(4-chloro-phenylsulfonyl) -amino] -benzoic acid [4- (6-trifluoromethoxy-benzothiazolyl-2-oxy) -anilide]; and the

4-chloro-2 - [(4-chlorophenyl-sulfinyl) amino] benzoic acid [4- (6-trifluoromethoxy-2-benzothiazolyl) anilide).

It has now been found that, surprisingly, the novel compounds of formula (I) according to the invention exhibit a very favorable spectrum of action against animal parasitic worms, particularly those that parasitize in warm-blooded animals, in particular mammals. The compounds of formula (I) are useful against nematodes, tapeworms and sucking worms. In addition, these compounds are also distinguished by their activity against worms resistant to benzimidazole, particularly thiabendazole (thiabendazole's chemical name is 2- (thiazol-4-yl) benzimidazole).

Compounds of formula (I) are prepared by:

a) reacting a compound of Formula II with a benzenesulfonic acid halide of Formula reakció (Scheme A); obsession

b) reacting a compound of Formula IV with a compound of Formula V (Scheme B), the substituents R1-Rn of Formula II, Formula III, Formula IV, and Formula V; in formula (III) X is a halogen atom, preferably a chlorine or bromine atom, especially a chlorine atom, and in the formula IV a halogen atom (preferably a chlorine or bromine atom), a hydroxy group or a suitable leaving group reacting with an amino group.

As the base for the reaction of the compounds of the formulas II and III and of the formulas IV and V, for example, tertiary amines such as triethylamine, trimethylamine, tripropylamine, N-methylpiperidine, 1,4-diazabicyclo [2.2. .2] octane, pyridine and pyridine bases such as 4-dimethylaminopyridine, 4-pyrrolidylaminopyridine, picoline, lutidine and an alkali metal or preferably alkali metal alkanolate with lower alkanols, such as sodium or potassium metal diolate, propanolate. ethanolate, n-butanolate, isobutanolate or tert-butanolate. A preferred base is pyridine.

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Suitable solvents or diluents include the following aprotic solvents: aliphatic and aromatic hydrocarbons such as benzene, toluene, xylene, petroleum ether; halogenated hydrocarbons such as chlorobenzene, methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, tetrachloroethylene; ether and ethereal compounds such as dialkyl ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, anisole, dioxane, tetrahydrofuran; nitriles such as acetonitrile, propionitrile; N, N-alkylated amides such as dimethylformamide; dimethyl sulfoxide; ketones such as acetone, diethyl ketone, methyl ethyl ketone and mixtures of such solvents. In some cases, the base itself may serve as a solvent.

The reaction temperature is usually -20 to +150 ° C, preferably 0 to 100 ° C. In the case where A in the formula (IV) is hydroxy, a condensing agent such as dicyclohexylcarbodiimide may be used.

The manufacturing processes described, including all the steps, are an important part of the present invention.

The compounds of formula (II) and salts of these compounds can be converted into end products.

The compounds of formula (II) may also be prepared by a variety of processes, for example from a compound of formula (VI)

(i) hydrogenation in the presence of a suitable hydrogenation catalyst; or (ii) chemical reduction; or (iii) reacting a compound of formula (VII) with a compound of formula (V): wherein R, -R, given for formula (I).

Reactions (i) and (ii) are carried out under normal pressure and preferably in the presence of an inert solvent or diluent, in particular one of the above ethers or ether-like compounds, an ester such as ethyl acetate, propyl acetate or butyl acetate or an alcohol, e.g. alkanols such as methanol, ethanol, propanol and the like. carried out. Generally, temperatures of from 0 to 80 ° C, preferably from 10 to 50 ° C, are employed.

The catalyst used in process (i) is, for example, a carbon-based rhodium catalyst or Raney nickel.

The chemical reduction according to (ii) can be carried out, for example, in the Sn (II) chloride / HCl system.

Reaction (iii) is preferably carried out in the presence of a polar inert organic solvent such as N, N-dimethylformamide, Ν, Ν-dimethylacetamide, dimethylsulfoxide, dioxane, butanone, tetrahydrofuran or dimethoxyethane. the temperature ranges from -10 ° C to +150 ° C, preferably from 0 ° C to 100 ° C.

The compounds of formula VI are novel. These can be prepared by reacting a compound of formula VIII with a compound of formula V (Scheme D), in which the hydroxy group A or a reactive leaving group such as a halogen, preferably chlorine or bromine, or an activated an ether group such as an alkoxycarbonyloxy group. This reaction is preferably carried out in an inert organic solvent such as benzene, toluene, methylene chloride, ether, dimethylformamide, dimethylsulfoxide, tetrahydrofuran, acetonitrile or acetone, preferably in the presence of a base such as triethylamine, pyridine or picoline. The reaction temperature is -20 to 150 ° C, preferably 0 to 50 ° C. When A is hydroxy, the reaction may also be carried out in the presence of a condensing agent such as dicyclohexylcarbodiimide.

Compounds of formula (V) are known or may be prepared, for example, by reaction of a compound of formula (IX) with a compound of formula (X) wherein R ₃ , R ₅ , R ₆ , R ₁₀ and R _n are as defined for formula (I). and Q is a conventional leaving group. The reaction temperature ranges from 0 to 200 ° C, preferably from 10 to 150 ° C, and is carried out in a polar inert solvent such as Ν, Ν-dimethylformamide, Ν, Ν-dimethylacetamide, preferably dimethylsulfoxide. in the presence of an inorganic base such as sodium carbonate, potassium carbonate, preferably potassium hydroxide. The reaction water may be removed from the reaction mixture using a vehicle such as methylene chloride, toluene or benzene.

In formula X, Q is a conventional leaving group, such as a halogen atom, especially a chlorine, bromine or iodine atom, a sulfonyloxy group, especially a benzenesulfonyloxy, p-toluenesulfonyloxy or a lower alkylsulfonyl group. represents an oxy group, preferably a mesyloxy group.

The compounds of formula (VII) are preferably obtained by oxidation of a compound of formula (XI).

This preparation is known from German Patent No. 2,925,175 and from Angewandte Chemie 92, 196 (1980).

The compounds of formula XI and their methods of preparation are known and may be prepared by methods known to those skilled in the art (see Houben-Weyl, Vol. 7/4, p. 5 et seq.).

Compounds of formula (IV) wherein A is hydroxy may be obtained by saponification of a compound of formula (XII) or (XIII) wherein B is methoxy or ethoxy.

Said saponification may preferably be carried out with an inorganic base such as sodium hydroxide or potassium hydroxide in the presence of a solvent such as water and / or alcohol, preferably methanol or ethanol (see Houben-Weyl, Vol. 9, p. 609 et seq.).

Compounds of formula (IV) wherein the reactive leaving group A, for example, wherein A is hydroxy, may be prepared by methods known to those skilled in the art.

The compounds of formula XII are novel.

(XII) and (XIII) with compounds of formula can be obtained by reacting a compound (XIV) wherein B, R, and R ₂ are as defined above, (III)

The compound of formula (XIV) is reacted with a compound of formula (XIV) and, when the substituent at the 3-position of the compound of formula (XIV) is substituted, a mixture of the compound of formula (XII) and XIII may be formed. When the 3-position of the compound of formula (XIV) is free, almost exclusively the compound of formula (XIII) is obtained.

Preferably, the aforementioned reactions are carried out under the conditions described for reaction A) (Π + III → I). Compounds of formula (XIV) may be obtained by analogous procedures, for example, as described in Tetrahedron 33, 217 (1977) or in German Patent No. 3,001579.

The starting compounds of formulas (III), (VIII), (X), (XI), (XIII) and (XIV) are known or may be prepared in a manner known per se.

The invention also relates to a method for the prophylactic protection of animals against parasitic worms, wherein the active ingredient or the composition containing the active ingredient is administered orally or injected into a feed or drinking water, or in solid or liquid form, or as a detergent. in the form of an animal.

Endoparasites in warm-blooded animals, namely worms, cause great damage. The animals on which these parasites colonize not only grow slowly but also have significant physiological damage, which can lead to death. It is therefore of great importance to develop drugs that can be used to combat worms and their developmental stages and to prevent the establishment of these parasites. Particularly dangerous are worm diseases caused by nematodes, tapeworms and sucking worms in the gastrointestinal tract and other organs, and especially in ruminants such as sheep, cattle and goats, and horses, pigs, cats, dogs, cats and dogs.

Worm-borne diseases are chronic and, above all, epidemic, can cause significant damage to herds. This is reflected, among other things, in a reduction in performance, a decrease in resistance and increased mortality. The fight against worm disease and the prevention of the disease are therefore paramount tasks in order to prevent or reduce this type of damage, which is of major economic importance.

As used herein, the term "poisons" includes in particular parasitic worms belonging to the genus Plathelminthes, such as tapeworms (Cestoidea) and nematodes (trematoda), and nematodes (nematodes and their relatives), and the gastrointestinal tract and other organs. (e.g., liver, lung, kidney, lymphatic vessels, blood, etc.) tapeworms, sucking worms and cylindrical worms. Although a number of anthelmintic agents have been known to be recommended for the control of various worm species, they are not completely satisfactory, either because they cannot work at their tolerable dose in accordance with their spectrum of action, or because the therapeutically effective dose exhibits undesirable side effects or properties. In this context, the increased resistance to specific groups of active substances today is playing an increasingly important role. For example, the albendazole described in the literature [British Patent No. 1,464,326; Am. J. Vet. Gap. 38: 14251426 (1977); Am. J. Vet. Gap. 37, 1515-1516 (1976); Am J, Vet. Gap. 38: 807-808 (1977); Am. J. Vet. Gap. 38, 1247-1248 (1977)], although having a narrow anthelmintic spectrum of action in ruminants, its activity against benzimidazole-resistant nematodes and adult moths is unsatisfactory, as the highly pathogenic form of the latter worm is primarily pathologically important in the host does not attack.

Surprisingly, it has been found that the active compounds of the formula I not only exhibit intense broad-spectrum anthelmintic activity against nematodes, tapeworms and whitetails, as mentioned above, but also have the advantage of their toxicity in warm-blooded species.

The novel active compounds of formula I according to the invention include, for example, nematodes belonging to the order Rhabditida, Ascaridida, Spirurida and Trichocephalida (KI Skrajabin), tapeworms belonging to the order Cyclophyllidae and Pseudophyllidae (belonging to Ward le and Mc Leod) and Digenea. can be used against domestic and farm animals such as cattle, sheep, goats, horses, pigs, cats, dogs and poultry. The compounds may be administered to the animals as a single dose or repeatedly, with doses varying from 1 to 500 mg / kg body weight, depending on the species of animal. In some cases, prolonged-dose administration may provide a better effect or a lower dose may be sufficient.

The agents according to the invention, wherein the active compounds of the formula I are brought into contact with liquid and / or solid formulation aids by gradual mixing and / or milling, are prepared in such a way as to optimally exert anthelmintic activity appropriate to the application.

The forming can be carried out by kneading, granulating and optionally pressing (pellets).

Formulation aids include, for example, solid carriers, solvents and, optionally, surfactants (surfactants).

Solid carriers such as kaolin, talc, bentonite, common salt, calcium phosphate, carbohydrates, cellulose powder, cotton seed meal, polyethylene glycol ether,

Optionally a binder such as gelatin, soluble cellulose derivatives, optionally with the addition of surfactants such as ionic or nonionic dispersants; and natural rock flour such as calcite, mentmorillonite or attapulgite. In order to improve the physical properties, a high degree of dispersion of silica or a highly dispersed polymer may be used. Porous types such as pumice, brick, sepiolite or bentonite are used as granular adsorbent granule carriers, for example, chelate or sand. In addition, many inorganic or organic pre-granulated materials, in particular dolomite or finely milled plant material, can be used.

As a solvent, aromatic hydrocarbons, in particular C8-C12 fractions thereof, such as xylene mixtures or substituted naphthalene, phthalic acid esters such as dibutyl or dioctyl phthalate; aliphatic hydrocarbons such as cyclohexane or paraffins, alcohols and glycols, and their ethers and esters such as ethanol, ethylene glycol, ethylene glycol monomethyl or ethyl ether, ketones such as cyclohexanone, highly polar solvents such as N-methyl-2- pyrrolidone, dimethyl sulfoxide or dimethylformamide; and optionally epoxidized vegetable oils such as epoxidized coconut oil or soybean oil and water.

Depending on the active compounds of formula (I) to be formulated, the surfactant compounds include nonionic, cationic and / or anionic surfactants with good emulsifying, dispersing and wetting properties. The term "surfactant" includes "surfactant flies".

Suitable anionic surfactants include so-called water-soluble soaps and water-soluble synthetic surfactants.

Among the soaps, alkali metal, alkaline earth metal or optionally substituted ammonium salts of higher fatty acids (10-22), such as sodium or potassium salts of oleic or stearic acid, or natural fatty acids such as coconut or tallow may be used.

Synthetic surfactants, in particular fatty sulfonates, fatty sulfates, sulfonated benzimidazole derivatives or alkylaryl sulfonates are frequently used.

Fatty sulfonates or sulfates usually exist in the form of alkali metal, alkaline earth metal or optionally substituted ammonium salts, and the alkyl moiety of the acyl groups also has from 8 to 22 carbon atoms, such as lignin sulfonic acid, fatty acid dodecyl calcium salts. Salts of sulfuric acid esters and sulfonic acids of fatty alcohol ethylene oxide adducts are also mentioned. The sulfonated benzimidazole derivatives preferably contain 2 sulfone groups and a C 8 -C 22 fatty acid residue. Alkylarylsulfonates are, for example, sodium, calcium or triethanolamine salts of dodecylbenzenesulfonic acid, dibutylnaphthalenesulfonic acid or a naphthalenesulfonic acid formaldehyde condensation product.

Suitable formulation aids include the appropriate phosphates, such as the salt of the phosphoric acid ester of a p-nonylphenyl (4-14) ethylene oxide adduct or a phospholipid.

Preferred nonionic surfactants are the polyglycol ether derivatives of aliphatic or cycloaliphatic alcohols, saturated or unsaturated fatty acids and alkyl phenols having from 8 to 20 carbon atoms in the aliphatic hydrocarbon moiety and from 6 to 18 carbon atoms in the alkyl phenol moiety. contain.

Other suitable nonionic surfactants include water-soluble C20-C10 alkyl polypropylene glycol, polypropylene glycol, ethylene diaminopolypropylene glycol and ethylene glycol ether having from 20 to 250 diethylene glycol ether groups and from 10 to 100 propylene glycol ether groups. These compounds generally contain from 1 to 5 ethylene glycol units per propylene glycol unit.

Examples of nonionic surfactants include nonyl phenol polyethoxyethanol, castor oil polyglycol ether, polypropylene polyethylene oxide adduct, tributyl phenoxy polyethoxyethanol, polyethylene glycol and octylphenoxy polyethoxyethanol.

Other fatty acid esters of polyoxyethylene sorbitan such as polyoxyethylene sorbitan trioleate are also contemplated.

Cationic surfactants are predominantly quaternary ammonium salts having at least one C8-C22 alkyl group as a substituent on the nitrogen atom and, as a further substituent, a lower alkyl, optionally halogenated alkyl, benzyl or low-hydroxyalkyl group. The salts are preferably halides, methylsulfates or ethylsulfates, for example stearyltrimethylammonium chloride or benzyldi (2-chloroethyl) ethylammonium bromide.

Commonly formulated surfactants are described, inter alia, in "McCutcheon's Detergents and Emulsifiers Annual" by MC Publishing Corp., Ridgewood New Jersey, 1981; H. Stache, Tensid-Taschenbuch, Cári Hanser Verlag, Munich / Wien, 1981.

Suitable binders for tablets and boluses are chemically modified water and alcohol soluble polymeric natural substances such as starch, cellulose or protein derivatives such as methylcellulose, carboxymethylcellulose, ethylhydroxyethylcellulose. proteins such as casein, gelatin and the like; and synthetic polymers such as polyvinyl alcohol, polyvinylpyrrolidone and the like. The tablets also contain fillers such as starch, microcrystalline cellulose, sugar, milk sugar, lubricant and disintegrant.

When the anthelmintic is formulated as a feed concentrate, the binder may be, for example, a feed grain or a protein concentrate. Such a feed concentrate or agent may contain, in addition to the active ingredient, additives, vitamins,

They may contain antibiotics, chemotherapeutic agents, pesticides, in particular bacteriostatic, fungistatic, coccidiostatic or hormonal preparations, anabolic agents or substances which may promote growth, affect the quality of the meat or are otherwise required by the body. When the agent or the active ingredient of the formula (I) contained therein is directly added to the feed or to the drinking water, it is preferred that the finished feed or drinking water be present in an amount of approx. Contains between 0.0005 and 0.02% (5-200 ppm) of active ingredient.

The agent of the invention may be administered orally, parenterally, succubutaneously or topically to the animal in the form of solutions, emulsions, suspensions, powders, tablets, boluses and capsules.

The anthelmintic agents according to the invention are usually present in an amount of from 0.1 to 99% by weight, in particular from 0.1 to 95% by weight, of the active compound of the formula 1 and 99.9 to 1% by weight, especially 99.9 to 5% by weight of solid or liquid additives, in addition they contain from 0 to 25% by weight, in particular from 0.1 to 25% by weight, of a surfactant.

While the commercially preferred concentrate is preferred, the user will usually use a diluted agent.

Such agents may also contain additional additives such as stabilizers, antifoams, viscosity regulators, binders, adhesives, and other active ingredients to achieve special effects.

User-anthelmintic agents of this type are also within the scope of the present invention.

The following examples are intended to illustrate the invention in greater detail, but are not intended to be limiting.

1. Production Examples

Procedure A)

1.1. Preparation of 5-chloro-2 - [(4-chlorophenylsulfonyl) amino] benzoic acid [4 '- (6-trifluoromethoxybenzothiazole-2-oxy) anilide]

a) 5-Chloro-2-nitrobenzoyl chloride

80.6 g of 5-chloro-2-nitrobenzoic acid and 58.2 ml of thionyl chloride are heated at 90 ° C for 2 hours. The excess thionyl chloride was evaporated in vacuo to give 87.1 g of 5-chloro-2-nitrobenzoyl chloride.

b) 5-Chloro-2-nitrobenzoic acid [4 '- (6-trifluoromethoxybenzothiazol-2-oxy) anil]

To a solution of 8.1 g of 5-chloro-2-thienylbenzoyl chloride in 150 ml of methylene chloride was added 14.4 g of 4- (6-trifluoromethoxybenzothiazolyl-2-oxy) aniline in 30 minutes and

A solution of triethylamine (7.2 ml) in methylene chloride (150 ml) was added. After stirring at room temperature for 20 hours, the solvent was stirred at room temperature for ca. 80% are removed. The resulting crystalline material is suspended in diethyl ether and the precipitated crystals are filtered off, washed first with 2N hydrochloric acid and then with water. The material was resuspended in diethyl ether to give 10.8 g of purified 5-chloro-2-nitrobenzoic acid [4 '- (6-trifluoromethoxybenzothiazolyl-2-oxy) anilide]. ° C.

c) 2-Amino-5-chlorobenzoic acid [4 '- (6-trifluoromethoxybenzothiazolyl-2-oxy) anilide]

8.5 g of 5-chloro-2-nitrobenzoic acid [4 '- (6-trifluoromethoxybenzothiazolyl-2-oxy) anilide] are dissolved in 170 ml of tetrahydrofuran and 7 g of Raney are added at room temperature for 16 hours. in the presence of a nickel-ethanol complex under hydrogen atmosphere. The reaction mixture was then filtered and the solvent was distilled off from the filtrate. The residual crude product is suspended in hexane and the crystals obtained after filtration of the solvent are dried. 7.1 g of 2-amino-5-chlorobenzoic acid [4 '- (6-trifluoromethoxybenzothiazolyl-2-oxy) anilide] are isolated, m.p. 151-154 ° C.

d) 5-Chloro-2 - [(4-chloro-phenylsulfonyl) -amino] -benzoic acid [4 '- (6-trifluoromethoxy-benzothiazolyl-2-oxy) -anilide]

To a solution of 2-amino-5-chlorobenzoic acid [4 '- (6-trifluoromethoxy-benzothiazolyl-2-oxy) -anilide] in 4.0 g of pyridine in 8.3 ml was cooled to 0 ° C. 4-Chlorobenzenesulfonic acid chloride is added. After stirring for 16 hours at room temperature, the mixture was diluted with 300 ml of diethyl ether and 50 ml of methylene chloride to give a solution of 100-100 ml of 2N hydrochloric acid, water, saturated sodium bicarbonate solution and saturated sodium hydroxide solution. chloride solution. The organic phase is then dried over magnesium sulfate and evaporated. The crystalline residue was recrystallized from a mixture of diethyl ether and hexane. 3.3 g of 5-chloro-2 - [(4-chlorophenylsulfonyl) amino] -benzoic acid [4 '- (6-trifluoromethoxybenzothiazolyl-2-oxy) anilide are obtained, m.p. -171 ° C.

Procedure B

1.1 3,5-Dichloro-2 - [(4-chlorophenylsulfonyl) amino] benzoic acid [4 '- (6-trifluoromethoxybenzothiazolyl-2-oxy) anilide]

4.0 g of 3,5-dichloro-2 - [(4-chlorophenylsulfonyl) amino] benzoic acid are suspended in 10 ml of thionyl chloride. The reaction mixture was heated at reflux for 4 hours and then excess thionyl chloride was distilled off. The residue was evaporated twice with 20 ml of toluene twice. The crude acid chloride was dissolved in methylene chloride (20 mL). To this solution while cooling with ice-water was slowly added 3.67 g of 4- (6-trifluoromethoxybenzothiazolyl-2-oxy) aniline (m.p. 78-80 ° C) and 2 ml of triethylamine in 30 ml of methylene chloride. solution is added dropwise. After the addition was complete, the mixture was diluted with methylene chloride (20 mL) and stirred at room temperature for 22 hours. The precipitated solid was filtered off and washed with methylene chloride. The crude product was washed with 2N hydrochloric acid and water; the product thus purified is taken up in 50 ml of methanol, stirred, the solvent is filtered off and the purified crystalline material is dried. 4.36 g of the title compound are obtained, m.p. 297-298 ° C.

The following compounds can be prepared as described above. The list is by no means restrictive.

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Table 7 Compounds of formula (Ia)

Number of compound R. r ₂ R.i r ₄ r ₅ ^r 6 r ₇ rr The interface of Hetocsoporl Compound Melting point [° C] process 1.1 5-Cl H H H H H 4-C1 H 4 / \ '\ - 'II 1 167-171 THE 1.2 5-Cl H H H H H 4-Cl H 4 M> C1 / W -! <II 1 221-223 THE 1.3 5-C1 H H H H H 4-Cl H 4 /\THE. W \ i 225-226 THE 1.4 5-Cl 3-C1 H H H H 4-Cl H 4 —R n ii V'Ao, 297-298 B 1.5 5-C1 H H H H H 4-Cl H 4 / \ A / ^C1 -; ni 245-247 B 1.6 5-Cl 3-Cl H II H H 4-Cl H 4 / \ '\ .. v v. > 330-334 B 1.7 5-Cl H H H H 4-Cl H 4 / \ '\ - · <II 1 Y'A ,,, 198-200 B

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Number of compound Ri r ₂ R ARC Rs R _f , r ₇ rr Location of the Helo Group Vegyiilet Op. ['C] process 1.8 5-SCH, H II 1-1 1-1 H 4-Cl H 4 / \ 'X - <yj v \ _CFJ 123-126 THE 1.9 5-Cl H w H H H 4-Cl H 4 / ν \ / ^η -Z || I v'v ' 178-180 B 1.10 5-C1 H H H H H 4-Cl H 4 /\THE" - <y i. ν v \ live ... 242-243 B 1:11 5-Cl H 41 H H H 4-Cl H 4 V ¹ A / \ / ^oclb - <y! V v 208-212 B 1:12 5-C1 H 11 H 2-F H 4-Cl 11 4 / \ / \ Vv \ _CF) 214-215 B 1:13 5-Cl H 11 II II H 4-Cl H 4 Ζ ^Νχ Ζ ”^ Z ° ^X. _Z II | | v \ A _o z. 225-227 B 1:14 5-F H H H H H 4-Cl 1-1 4 / V \ '\ !! · ί s ^z \ _CFl 187-188 THE

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Number of compound Ltd. r ₂ R? R ' Rs ^r 6 r ₇ Rs The point of attachment of the Hetero group Compound Melting point [° C] process 1:15 5-F 3-F H H H H 4-Cl H 4 / \ '\ —C ϊ i ^X OCFj 278-280 THE 1:16 4-C1 H H H H H 4-C1 H 4 / \ '\. - • 'II 1 · · VV \ cr, 180-183 THE

2. Preparation Examples (% = Weight%) 2.1 Emulsion concentrate the) b) c) Table I active substance 25% calcium dodecyl 40% 50% 25 benzene sulfonate 5% 8% 6% castor oil polyethylene ethylene glycol ether (36 moles of ethylene) oxide) 5% tributyl phenol - 30 polyethylene glycol ether (30 moles ethylene oxide) 12% 4% 35 cyclohexanone 15% 20% xylene mixture 65% 25% 20% From the above concentrate an emulsion of the desired concentration with water can be prepared, by dilution with 2.2 Solutions the) b) c) d) 40 Table I- pond material 80% ethylene glycol motor 10% 5% 95% nomethyl ether 20% - - 45 polyethylene glycol (MG 400) 70%. N-methyl-2-pinolidone epoxidized coconut 20% - Walnut oil gasoline (RP range 160— 1% 5% 50 190 ° C) (MG = molecular weight) 94% - The solutions are suitable the shape of the smallest drop- 55 for administration. 2.3 Granules the) b) Active ingredient in Table I 5% 10% 60

kaolin 94% highly dispersed silica 1% attapulgite - 90%

The active ingredient is dissolved in methylene chloride, sprayed onto the support and the solvent is then removed by distillation in vacuo. Such granules may be incorporated into the feed.

2.4 Dusting agent the) b) Table I - material 2% 5% high dispersion co- Vasavi 1% 5% talc 97% - kaolin - 90%

Intimate mixing of the carriers with the active ingredient provides a ready-to-use powder.

2.5 Water-dispersible powder mixture

a) b) c)

Table I-

active compound in Sodium Iignin- 25% 50% 75% sulfonate 5% 5% - oleic acid Sodium di- isobutyl naphthalene 3% 5% sulfonate octylphenol polyethylene glycol ether (7-8 moles ethylene) 6% 10% oxide) · nagydiszperzitás - 2% - degree of silica 5% 10% 10% kaolin 62% 27% - The active ingredient ot the additives well e stir and a proper one mill ground. This way we get a sprayable powder,

what concentration can be diluted to the desired suspension.

HU 207 332 Β

2.6 Emulsion concentrate

a) b) c)

Active ingredient in Table I 10% 8% 60% octylphenol polyethylene glycol ether (4-5 moles ethylene oxide) 3% 3% 2% castor oil polyethylene glycol ether (35 moles ethylene glycol)

oxide) 4% 5% 4% cyclohexanone 30% 40% 15% xylene mixture 50% 40% 15% water 3% 4% 4%

This concentrate can be diluted with water to form an emulsion of any desired concentration.

2.7 Dusting agent the) b) Table I - material 5% 8% talc 95% - kaolin - 92%

The active ingredient is mixed with the carrier and ground in a suitable mill ready for use

a powder is obtained. 2.8 Granules Active ingredient in Table I 10% Sodium ligninsulfonate 2% carboxymethyl cellulose 1% kaolin 87%

The active ingredient is mixed with the additives, ground and moistened with water. This mixture was extruded and finally air-dried.

2.9 Granules Active ingredient in Table I 3% polyethylene glycol (MG 200) 3% kaolin 94% (MG = molecular weight)

The finely powdered active ingredient is uniformly applied in a blender to the kaolin moistened with polyethylene glycol. In this way, a powder-free coated granulate is obtained.

2:10. Szuszpenziókoncentrálum

Active ingredient in Table I 40% ethylene glycol 10% non-phenol-poly-ethylene- glycol ether (15 moles ethylene) oxide) 6% Sodium ligninsulfonate 10% carboxymethyl-target lu 1 oz 1% 37% aqueous formal formaldehyde solution 0.2% silicone oil 75% aqueous in the form of an emulsion 0.8% water 32%

2.11 Pills and boluses

Active ingredient in Table I 33.00% methylcellulose 0.80% high dispersion co- Vasavi 0.80% cornstarch 8.40% 51. Lactose (crystalline 22.50% cornstarch 17.00% microcrystalline cellulose 16.50% magnesium stearate 1.00%

I. Methylcellulose is mixed with water and allowed to swell; the silica is added to the above mixture and a homogeneous suspension is prepared. The active ingredient is mixed with corn starch. In this mixture, the aqueous suspension is worked up and kneaded to form a mass. This mass is granulated through a 12 M sieve and dried.

II. The four excipients are well mixed.

III. I and II. The materials obtained in Phase II are mixed and compressed into pills or boluses.

3. Biological Examples

The anthelmintic effect is demonstrated by the following tests:

3.1. Tests on sheep infected with nematodes such as Haemonchus contortus and Trichostronylus colubriformis.

The active ingredient is administered in the form of a suspension in sheep, which has been artificially infected with gastric worms, such as Haemonchus contortus and Trichostrongylus colubriformis, by gavage or by injection into the stomach. 1-3 animals are used per dose. Each sheep is treated with a single dose.

The first evaluation is made by comparing the number of eggs isolated from the sheep's feces before and after treatment.

Sheep are killed and autopsied 7-10 days after treatment. Evaluation is done by counting the number of worms remaining in the treated animal. Simultaneously and similarly infected but untreated sheep serve as a basis for comparison.

The active ingredients in Table 1 are effective at doses of 50 mg / kg or less in sheep, which represents a 90% or greater reduction in colonies compared to the untreated but infected control group. Compounds of formula I, e.g. Compound No. 1 is effective at a dose of 20 mg / kg body weight and reduces the number of colonized nematodes by more than 90%.

3.2. Studies in sheep infected with Fasciola hepatica

The active ingredient is administered as a suspension to the sheep previously artificially infected with Fasciola hepatica by gavage or injection into the stomach. Three animals per dose are used. Each sheep is treated with a single dose.

The finely powdered active ingredient is intimately mixed with the additives. This gives a suspension concentrate which can be diluted with water to form a suspension of any desired concentration.

HU 207 332 Β

The first evaluation is made by comparing the number of eggs isolated from the sheep's feces before and after treatment.

Sheep are sacrificed 3-4 weeks after treatment and autopsied. The evaluation is done by counting the number of liver flukes remaining in the bile ducts after treatment. Co-infected but untreated sheep serve as a basis for comparison. The difference in liver counts observed between the two groups gives the degree of efficacy of the test substance.

Suspensions with the active compounds of Table I gave good results, that is, a dose of 50 mg / kg or less reduced the number of colonies by at least 90%.

Claims (4)

PATENT CLAIMS A process for the preparation of a compound of formula (I): wherein R | halogen or -SR wherein R is C 1-6 alkyl; R _{2 is} hydrogen or halogen; R _{3 is} hydrogen; R _{4 is} hydrogen; R _{5 is} hydrogen or halogen; Rg is hydrogen; R _{7 is} halogen; R _{8 is} hydrogen; R _{9 is} hydrogen; R 10 is hydrogen, halogen, trifluoromethyl, trifluoromethoxy, or nitro; R _{n is} hydrogen, halogen, C 1-2 haloalkoxy, or C 1-2 alkoxy; obsession Rio and R j together form a -O (CH _{2) 2} -O- bridge having the formula, whereby the benzothiazolyl group 4-position and the physiologically tolerated acid addition salts thereof, characterized in that a) reacting a compound of formula II with a compound of formula III; in the formulas R (-R) | and X is halogen, preferably chlorine or bromine, especially chlorine; or b) reacting a compound of formula IV with a compound of formula V; the formulas, R _R R _h is as defined above and A is halogen, preferably chlorine or bromine, hydroxyl or a reactive amino group suitable leaving group, reactions -20 - carried out at 150 ° C temperature range, if desired, one (I) and The compound of formula I is converted into an acid addition salt which is physiologically tolerated by an acid. A process for the preparation of an anthelmintic, characterized in that a compound of formula (I) or a physiologically acceptable acid addition salt thereof prepared by the process of claim 1, wherein R) is halogen or -SR, wherein R 1-6 C 1 -C 6 alkyl; R _{2 is} hydrogen or halogen; R _{3 is} hydrogen, R _{4 is} hydrogen; R _{5 is} hydrogen or halogen; R _{6 is} hydrogen; R _{7 is} halogen; R _{8 is} hydrogen; R _{9 is} hydrogen; R 10 is hydrogen, halogen, trifluoromethyl, trifluoromethoxy, or nitro; R 1 is hydrogen, halogen, C 1-2 haloalkoxy or C 1-2 alkoxy; obsession R, o and R, | together form a bridge of the formula -O (CH ₂ ) ₂ O-, wherein the benzothiazolyl group at position 4 as an active ingredient is gradually mixed or ground with physiologically tolerable liquid or solid formulation aids. 3. The process according to claim 2, wherein the active ingredient is one of the following compounds of formula (I): 5-Chloro-2 - [(4-chloro-phenylsulfonyl) -amino] -benzoic acid [4- (6-trifluoromethoxy-benzothiazolyl-2-oxy) -anilide] -eth, 5-chloro-2 - [(4) -chlorophenylsulfonyl) amino] benzoic acid [4- (6-fluoro-5- (or -7) -chlorobenzothiazolyl-2-oxy) amide], 5-chloro-2 - [(4-chlorophenyl-sulfonyl) amino] benzoic acid [4- (6-chloro-2-benzothiazolyl) anilide] eth, 3,5-dichloro-2 - [(4-chlorophenylsulfonyl) amino] benzoic acid [4- (6-trifluoromethoxybenzothiazolyl-2-oxy) anilide], or 4-Chloro-2 - [(4-chloro-phenylsulfinyl) -amino] -benzoic acid [4- (6-trifluoromethoxy-benzothiazolyl-2-oxy) -anilide].